CN1145623C - Imidazole derivatives as protein kinase inhibitors in particular egf-rthyrosine kinase - Google Patents
Imidazole derivatives as protein kinase inhibitors in particular egf-rthyrosine kinase Download PDFInfo
- Publication number
- CN1145623C CN1145623C CNB951976281A CN95197628A CN1145623C CN 1145623 C CN1145623 C CN 1145623C CN B951976281 A CNB951976281 A CN B951976281A CN 95197628 A CN95197628 A CN 95197628A CN 1145623 C CN1145623 C CN 1145623C
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- Prior art keywords
- phenyl
- chloro
- compound
- imidazol
- pyridine
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- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
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- 230000003204 osmotic effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
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- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical class [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cosmetics (AREA)
Abstract
Imidazole derivatives of general formula (I), wherein R<1>-R<8> each independently signify hydrogen, lower-alkyl, substituted lower alkyl, lower-alkenyl, lower-alkoxy, substituted lower alkoxy, lower-alkoxycarbonyl, halogen, hydroxy, amino, mono- or di(lower-alkyl)amino or nitro, and pharmaceutically usable salts thereof are protein kinase inhibitors and can be used as medicaments, e.g. for the control of hyperproliferative disorders such as atherosclerosis, psoriasis and tumors as well as of alopecia.
Description
The present invention relates to the new imdazole derivatives and the pharmaceutical salts thereof of following general formula:
R wherein
1Expression low alkyl group or halogen, R
2Expression hydrogen, hydroxyl, nitro, lower alkoxycarbonyl, two (low alkyl group) amino-low alkyl group, morpholino low alkyl group or 4-methylpiperazine base-low alkyl group, R
3Expression hydrogen or low alkyl group, R
5Expression amino or low alkyl group, R
7Expression hydrogen or low alkyl group, R
8The expression hydrogen or halogen.
Term used herein " low alkyl group ", no matter be independent form or array configuration, expression has the straight or branched alkyl group of 1-6 carbon atom, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl and n-hexyl.Term " halogen " or " halogen " comprise fluorine, chlorine, bromine and iodine.
Methyl and sec.-propyl are preferred low-grade alkyl groups.Chlorine is preferred halogen.
Preferred formula I examples for compounds is:
4-[5-(4-chloro-phenyl-)-2-(2,4, the 6-trimethylphenyl) imidazol-4 yl] pyridine,
4-[5-(3-aminomethyl phenyl)-2-(2,4, the 6-trimethylphenyl) imidazol-4 yl] pyridine,
3-chloro-2-[4-(4-chloro-phenyl-)-5-pyridin-4-yl-imidazoles-2-yl] aniline,
4-[5-(4-chloro-phenyl-)-2-(2, the 6-diisopropyl phenyl) imidazol-4 yl] pyridine,
3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl imidazoles-2-yl]-the mesitylene carboxylic acid methyl esters,
4-[3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl] morpholine,
[3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl] dimethylamine,
1-[3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl]-the 4-methylpiperazine,
4-[5-(4-chloro-phenyl-)-2-(2,4,6-trimethylammonium-3-nitrophenyl)-imidazol-4 yl] pyridine,
3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,
4-[5-(4-fluorophenyl)-2-(2-bromo-6-aminomethyl phenyl)-imidazol-4 yl]-pyridine.
The formula I compound that contains acidic functionality can form pharmaceutical salts with alkali, and these alkali are alkali metal hydroxide (as sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (as calcium hydroxide and magnesium hydroxide) and ammonium hydroxide etc. for example.The formula I compound that contains basic functionality can form pharmaceutical salts with acid.For this class salt, not only should consider the salt that mineral acid forms, also should consider the salt that organic acid forms, mineral acid is hydrochloric acid or Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid for example, and organic acid is acetate, tartrate, succsinic acid, formic acid, toxilic acid, oxysuccinic acid, Whitfield's ointment, citric acid, methylsulfonic acid, tosic acid etc. for example.
The present invention correspondingly relates to formula I compound and pharmaceutical salts itself and they thereof the application as therapeutic active substance, make the method for these compounds and salt thereof, the medicine that contains these compounds or salt, the preparation method of these medicines, the application aspect control disease of these compounds and salt thereof, or these compounds and the application of salt aspect preparation treatment and prophylactic medicine thereof, described disease is meant the hyperplasia disease especially, as atherosclerosis, psoriatic and tumour, and the treatment alopecia.
The pharmaceutical activity of The compounds of this invention can be determined according to its activity as kinases inhibitor and HaCaT inhibition of cell proliferation.Specifically, The compounds of this invention is the selective depressant of EGF-R ELISA (EGF-R) Tyrosylprotein kinase.
EGF-R is in some human malignant's disease, works as the growth of mammary cancer, liver cancer and prostate cancer with in shifting.
For whole known functions of EGF-R and activity, its tyrosine kinase activity is a deciding factor.Therefore, active inhibition can be counted as measuring the effectiveness of the therapeutic action of the hyperplasia disease (such as the cancer or the psoriatic of some type) of EGF-R mediation to this kind of enzyme by formula I compound.
Opposite with the activation of EGF acceptor in keratinocyte propagation, studies show that the activity of this receptor is the active negative modulator of hair follicle in the external and body.Therefore, give newborn mice (Moore etc., J.Endocrinol 88,293[1981]) and sheep (Chapman ﹠amp; Hardy, J.Biol.Sci.41,261[1988]) injection EGF suppressed its hair growth, and handle the human hair follicle of cultivating with EGF and can induce the catagen sample state that suppresses hair and generate (Philpott etc., J.Cell Sci.97,463[1990]).These discoveries show the inhibition meeting stimulating hair growth to the EGF-R Tyrosylprotein kinase, and the time length of the interior hair round-robin phase in vegetative period of extension body.
Detect according to the biological activity of following various detection models The compounds of this invention.
Tyrosine protein kinase
The inhibition of EGF receptor tyrosine kinase
The activity of EGF receptor tyrosine kinase is determined as follows: measure
32The phosphorylation thing of P mark from
32P-γ-ATP (10 μ M) is to substrate RR-scr peptide
*Transfer (0.75mM).Film fraction from people A431 is used as enzyme.According to Thom etc., Biochem.J.168,187 (1977) method is separated it, is kept in (4-6 milligram albumen/milliliter) under-75 ℃.Compound detects in 10%DMSO, and concentration is 0.001-100 μ M.The Tris damping fluid (25mM, pH7.4) in, 30 ℃ of down insulations 30 minutes, the Tris damping fluid comprises magnesium acetate (30mM), vanadic acid sodium (0.5mM), 0.5%BSA and 0.05%Triton X-100.With film in 2 μ M EGF, 4 ℃ of following preincubation 90 minutes.By adding the initial detection of enzyme (2 milligrams of membranins), by adding ice-cold KH
2PO
4(1M pH3.0) stops detecting.After centrifugal, the peptide that is labeled is separated among the excessive ATP from supernatant by reversed-phase HPLC.Collect the peptide fraction, in the β of standard counter or with radiometer (Berthold) on-line measurement radioactivity.The inhibition activity of test-compound suppresses required micro-molar concentration with 50% and represents (IC
50[μ M]).
*RR-scr peptide=[Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly]
P56
Ick
The inhibition of Tyrosylprotein kinase
P56
IckThe activity of Tyrosylprotein kinase is determined as follows: measure
32The phosphorylation thing of P mark from
32P-γ-ATP (10 μ M) is to substrate RR-scr peptide
*Transfer (0.75mM).P56
IckTyrosine people's reorganization p56
Ick(at expression in escherichia coli) is used as enzyme.Its purifying from solvable fraction is come out and be kept under-75 ℃ by the monoclonal anti scapus.Compound detects in 10%DMSO, and concentration is 0.001-100 μ M.The HEPES damping fluid (50mM, pH6.9) in, 30 ℃ of down insulations 30 minutes, the HEPES damping fluid comprises magnesium chloride (11mM) and 0.5%BSA.By adding the initial detection of enzyme, by adding ice-cold KH
2PO
4(1M pH3.0) stop to detect, centrifugal after, by reversed-phase HPLC the peptide that is labeled is separated among the excessive ATP from supernatant.Collect the peptide fraction, in the β of standard counter or with radiometer (Berthold) on-line measurement radioactivity.The inhibition activity of test-compound suppresses required micro-molar concentration with 50% and represents (IC
50[μ M]).
Serine/threonine protein kitase
The inhibition of cAMP dependent protein kinase (PKA)
The activity of PKA is determined as follows: use partially purified PKA from the pig brain (according to U.Kikkawa etc., Enzymology method 99,288,1983), measure
32The phosphorylation thing of P mark from
32P-γ-ATP (10 μ M) is to the transfer of substrate histone h1 (333 μ g/ml).(20mM, 2 μ M CAMP pH7.4) activate PKA with being dissolved in Tris HCl damping fluid.Compound detects in the DMSO/ damping fluid, and concentration is 0.001-100 μ M.By adding the initial detection of enzyme, under 32 ℃, carried out 2 minutes, stop detecting by adding 20% trichoroacetic acid(TCA) (containing 1%SDS and 1% trisodium phosphate).The protein precipitation that will contain radiolabeled histone by the nitrocellulose membrane filter, separates with excessive ATP.Radioactivity on the filter is determined with scintillometer.The inhibition activity of test-compound suppresses required micro-molar concentration with 50% and represents (IC
50[μ M]).
The inhibition of protein kinase C (PKC)
The activity of PKC is determined as follows: use partially purified PKC from the pig brain (according to U.Kikkawa etc., Enzymology method 99,288,1983), measure
32The phosphorylation thing of P mark from
32P-γ-ATP (10 μ M) is to the transfer of substrate histone h1 (200 μ g/ml).PKC is activated by phospholipid capsule bubble, this phospholipid capsule bubble be by with 0.05ml phosphatidylserine (10mg/ml) and 0.005ml diolein (10mg/ml) in 5ml Tris HCl damping fluid (20mM, pH7.4) the ultrasonic preparation of mixture in.Compound detects in the DMSO/ damping fluid, and concentration is 0.001-100 μ M.By adding the initial detection of enzyme, under 32 ℃, carried out 2 minutes, stop detecting by adding 20% trichoroacetic acid(TCA) (containing 1%SDS and 1% trisodium phosphate).The protein precipitation that will contain radiolabeled histone by the nitrocellulose membrane filter, separates with excessive ATP.Radioactivity on the filter is determined with scintillometer.The inhibition activity of test-compound suppresses required micro-molar concentration with 50% and represents (IC
50[μ M]).
The inhibition of HaCaT cell proliferation
HaCaT is the spontaneous not dead cell system of human keratinocyte (Boukamp etc., 1988), and it repeatedly is used for excess proliferative keratinocyte model system.[
3H]-thymidine mix the grown cell that is used to quantization cell cycle S phase.Cell and DEME/F12 nutrient solution have replenished 5%FCS, EGF (10 μ g/l), hydrocortisone (400 μ g/l), Toxins,exo-, cholera (8.5 μ g/l), Regular Insulin (5 μ g/l), L-glutamine (2mM) and penicillin/streptomycin with 3: 1 mixed culture in the nutrient solution.The nutrient solution of 200 μ l is placed on the microtitration flat board, makes each sample contain 5000 cells.When cultivating beginning, with 1 * 10
-8M to 1 * 10
-5Serial dilution rate in the M scope adds test-compound.Cell was cultivated 48 hours down at 37 ℃.Add in the end 6 hours [
3H]-thymidine (1mCi/ sample).Behind trypsin digestion and cell, the amount liquid scintillation counter measurement of the radioactivity that mixes.
These compounds are provided by following table to the vitro inhibition effect of selected protein kinase with to the restraining effect of HaCaT cell proliferation.
IC 50(μM) | |||||
Embodiment | Isolating enzyme | Cell | |||
EGF-R | p56 ICK | PCK | PKA | HaCaT | |
1 | 0.34 | 2.2 | >100 | 6.3 | 2 |
4 | 0.80 | 6.0 | >100 | 190 | 2 |
16 | 0.31 | 2.2 | n.t. | n.t. | 0.8 |
7 | 0.13 | 3.1 | 100 | 0.47 | 3.5 |
9 | 0.14 | 3.8 | 80 | 6.0 | 0.23 |
11 | 0.26 | 5.1 | >100 | 43 | 0.1 |
12 | 0.05 | 1.65 | 7.0 | 5.0 | 0.57 |
13 | 0.05 | 1.8 | 37 | 1.5 | 0.1 |
15 | 0.78 | 4.95 | n.t. | n.t. | 0.67 |
18 | 0.29 | 14 | 23 | 1.8 | 2 |
N.t.: do not detect
The hormesis of cell proliferation in the mouse hair follicle of cultivating
According to Buhl etc., J.Invest.Dermatol.92,315 (1989) methods of describing are separated and are also cultivated the mouse hair follicle.Obtain palpus hair part from the CD-1 mouse of 4 ages in days, hair follicle is separated with surrounding tissue carefully at microscopically.Hair follicle is cultivated in the M199 nutrient solution, and this nutrient solution contains 20%FBS, by among the DNA [
3H]-thymidine mix definite cell proliferation.Test-compound is dissolved among the DMSO, when cultivating beginning, with 1 * 10
-8M to 1 * 10
-5Serial dilution rate in the M scope adds.After 1 day, in nutrient solution, add 5 μ Ci/ml [
3H]-thymidine, again with hair follicle incubation 3 days.Clean hair follicle with phosphoric acid buffer subsequently, to remove uncorporated radioactivity, by being incubated overnight with alkali and DNA being dissolved.Mix the radioactivity liquid scintillation counter measurement of hair follicle DNA.
With the hormesis that compound and the mouse hair follicle incubation of embodiment 1 will cause on cell proliferation, when concentration was 0.3 μ M, DNA synthetic maximum value was 211 ± 17% (compared with the control).Produce the concentration (EC of DNA synthetic half maximal stimulation effect
50Value) is 0.1 μ M.The activity of the compound of embodiment 1 in this culture systems surpassed known trichogen (hypotrichotic agent).For example, synthetic 160 ± 15% (compared with the control), the EC of reaching of minoxidil hair follicle stimulating DNA
50Value is 200 μ M.
According to the present invention, formula I compound and pharmaceutical salts thereof can prepare as power: incite somebody to action wherein R
7And R
8The diketone of the following general formula that implication is the same:
With R wherein
1, R
2, R
3And R
5The aldehyde of the same following general formula of implication:
Under the condition that ammonia exists, react; the hydroxy-protective group that removal may exist; if the words that need; reactive group in the resulting formula I compound is carried out functionalized modification; and if the words that need; formula I compound is transformed into pharmaceutical salts, and the oh group in the compound of formula III can exist with protected form.
The reaction of formula II diketone, formula III aldehyde and ammonia can be carried out in a manner known way.For example, formula II diketone can with formula III aldehyde and ammonium acetate (a kind of reagent that discharges ammonia) in mineral acid (for example acetate), in the temperature (for example about 50 to 100 ℃) that raises reaction down.
According to the present invention, the hydroxyl of formula III compound can exist with protected form (for example as dibenzyl ether), can remove protection in a manner known way from reaction product, for dibenzyl ether, can be removed with shortening.
Formula II diketone and formula III aldehyde are known, and known mode that can describe with embodiment or similarly own with it prepares them.
The functionalized modification of reactive group comprises for example saponification of ester, and it is amino that nitroreduction becomes, and amino alkylation.These functionalized modifications can carry out in a manner known way, for example described the or similar with it mode of embodiment.
By the acidic cpd of formula I being transformed into pharmaceutical salts, by the basic cpd of formula I being transformed into pharmaceutical salts with acid treatment with alkaline purification.This class reaction can be carried out with known mode itself.
Formula I compound and salt thereof can be as for example medicines of pharmaceutical dosage forms.
Medicine can be in stomach and intestine, parenteral or topical application.The form of the medicine that is suitable for using in the stomach and intestine comprises for example tablet, capsule, dragee agent, syrup, suspension agent, solution and suppository.The medicine of infusion or injection solution form is suitable for parenteral and uses.
The dosage of the preparation of using is according to application mode and application approach and patient's needs and different.
When Orally administered, The compounds of this invention can be considered 0.1-100mg/kg every day for adult's dosage, is preferably 0.5-50mg/kg.
Preparation can be used with potion or multi-agent.Preferred administration form is the capsule that contains about 5-500mg activeconstituents.
Preparation can contain inert or pharmacodynamics active additive.For example, tablet can contain a series of wedding agents, weighting agent, carrier or thinner.Liquid preparation can exist with for example miscible solution form of easy and sterilized water.Except that activeconstituents, capsule can contain weighting agent or thickening material.In addition, can add the additive that tarts up, be used as the material of sanitas, stablizer, wetting Agent for Printing Inks, emulsifying agent usually, and the salt of regulating osmotic pressure, buffer reagent and other additives.
Carrier above-mentioned and thinner can comprise organic or inorganic substance, for example water, gelatin, lactose, starch, Magnesium Stearate, talcum, Sudan Gum-arabic, polyoxyethylene glycol etc.All used adjuvants all must be nontoxic during the preparation preparation.
For carrying out topical application, activeconstituents preferably uses with forms such as ointment, tincture, emulsifiable concentrate, solution, lotion, spray, suspension agent, gelifying agents.Ointment and emulsifiable concentrate and solution are preferred.The preparation that is suitable for topical application can prepare by mixing with nontoxic inert solid or liquid vehicle as the processed products of activeconstituents, and described carrier is suitable for topical application and is employed usually in this class preparation.
For topical application, appropriate dosage is about 0.1-10%, the solution of preferred 0.3-2%, and big 0.1-10%, ointment and the missible oil of preferred 0.3-2%.
If desired, can in preparation, sneak into antioxidant, as tocopherol, N-methyl-γ-tocopherylamine and tertiary butyl hydroxyanisol or tertiary butyl hydroxytoluene.
The following examples will illustrate in greater detail the present invention.
Embodiment 1
With 12.3 gram 1-(4-chloro-phenyl-)-2-pyridin-4-yl-second diketone and 7.4 grams 2,4, the mixture of 6-trimethylbenzaldehyde in 125 milliliters of acetic acid solutions that contain 40 gram ammonium acetates stirred 2 hours down at 100 ℃, was cooled to room temperature then.Mixture is poured in the mixture of 300 milliliters of frozen water and 200 milliliters of concentrated ammonia solutions, with ethyl acetate with mixture extracting three times.Behind anhydrous magnesium sulfate drying, solvent is volatilized to be fallen.Come the purifying resistates by on silica gel, carrying out chromatography, and resistates crystallized out from ethyl acetate, obtain 6.7 gram 4-[5-(4-chloro-phenyl-)-2-(2,4, the 6-trimethylphenyl) imidazol-4 yls with methylene chloride (9: 1)] pyridine, 275 ℃ of fusing points.
Embodiment 2-17
Be similar to embodiment 1 preparation following compounds:
(2.4-[5-4-fluorophenyl)-2-(2,4, the 6-trimethylphenyl) imidazol-4 yl] pyridine, fusing point 252-254 ℃ (ether),
(3.4-[5-4-chloro-phenyl-)-2-(2, the 6-3,5-dimethylphenyl) imidazol-4 yl] pyridine, fusing point 290-292 ℃ (ethyl acetate/hexane),
(4.4-[5-3-aminomethyl phenyl)-2-(2,4, the 6-trimethylphenyl) imidazol-4 yl] pyridine, fusing point 251-253 ℃ (ether),
(5.4-[5-4-chloro-phenyl-)-2-(2-chloro-6-aminomethyl phenyl) imidazol-4 yl] pyridine, fusing point>260 ℃ (acetone),
(6.4-[5-4-chloro-phenyl-)-2-(2-bromo-6-aminomethyl phenyl) imidazol-4 yl] pyridine, fusing point>260 ℃ (acetone/hexane),
(7.4-[5-4-chloro-phenyl-)-2-(2, the 6-diisopropyl phenyl) imidazol-4 yl] pyridine, fusing point>260 ℃ (acetone/hexane),
(8.4-[5-4-fluorophenyl)-2-(2-bromo-6-aminomethyl phenyl) imidazol-4 yl] pyridine, fusing point>260 ℃ (methylene dichloride),
9. methyl 3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-the mesitylene carboxylic acid ester, 228 ℃ of fusing points (ethyl acetate/sec.-propyl ethyl ester),
(10.4-[5-4-chloro-phenyl-)-2-(2,6-dimethyl-3-nitrophenyl) imidazol-4 yl] pyridine, fusing point 295-298 ℃ (ethyl acetate/hexane),
(11.4-[3-[5-4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl] morpholine, fusing point 239-240 ℃ (ethyl acetate),
(12.[3-[5-4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl] dimethylamine, 222 ℃ of fusing points (acetonitrile),
(13.1-[3-[5-4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl]-the 4-methylpiperazine, 280 ℃ of fusing points (ethyl acetate),
(14.3-[5-4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2, the 4-xylenol, fusing point>300 ℃ (ethanol),
(15.4-[5-4-chloro-phenyl-)-2-(2,4,6-trimethylammonium-3-nitrophenyl) imidazol-4 yl] pyridine, fusing point 295-299 ℃ (methanol/ethyl acetate),
(16.3-[5-4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2, fusing point>300 ℃ (ethanol),
17. (2RS, 6RS)-and (2R, 6S)-4-[3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl]-2,6-thebaine, fusing point 163-170 ℃ (ethyl acetate).
Embodiment 18
0.2 gram 4-[5-(4-chloro-phenyl-)-2-(2-chloro-6-nitrophenyl) imidazol-4 yl] solution of pyridine in 20 ml methanol, under the condition that 0.1 gram, 10% palladium carbon exists, by hydrogenation 2 hours.Filtration catalizer evaporates solution so that dry.Recrystallization obtains 0.1 gram 3-chloro-2-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl from ethyl acetate] aniline, fusing point 220-222 ℃.
Be not described used parent material among the embodiment 1-18 of its preparation method so far, can be according to method described below or similarly method preparation with it:
A. ethanone derivatives (formula II compound)
1-(4-chloro-phenyl-)-2-pyridin-4-yl-second diketone
(i) 37.8 grams, four potassium butyrates that 19.4 gram 4-picolyl isocyanic ester dropwise added stirring under-5 ℃ are dissolved in the solution that 400 milliliters of tetrahydrofuran (THF)s form.Mixture is handled with 23.1 gram 4-chlorobenzaldehydes, stirred 2 hours down at-5 ℃ again.Subsequently, under 0 ℃, dropwise add 19.7 gram acetate, filtering solid while stirring.Resistates is chromatography on silica gel, makes elutriant with methylene chloride (95: 5), recrystallization from dichloromethane/hexane.Obtain 25.0 gram (E/Z)-N-[2-(4-chloro-phenyl-)-1-pyridin-4-yl-vinyl] methane amide, fusing point 155-156 ℃.
(ii) with 39.0 gram (E/Z)-N-[2-(4-chloro-phenyl-)-1-pyridin-4-yl-vinyl] methane amide be dissolved in the solution that forms in 430 ml methanol at 0 ℃ down with 112 milliliters of concentrated hydrochloric acids processing.Mixture was stirred 16 hours down at 32-34 ℃.Mixture is cooled to 0 ℃ subsequently, it is dropwise added 82.2 gram potassium hydroxide on 0 ℃ of following stirring limit and is dissolved in the solution of 100 ml waters formation.Solid is by filtering, and recrystallization comes out from dichloromethane/hexane.Obtain 25.0 gram 1-(4-chloro-phenyl-)-2-pyridin-4-yl-ethyl ketones, fusing point 85-86 ℃.
(iii) 25 gram 1-(4-chloro-phenyl-)-2-pyridin-4-yl-ethyl ketones being dissolved in the solution that forms in 285 milliliters of dioxs handles with 20 gram tin anhydride.Mixture was stirred 1 hour down and filters at 100 ℃.Solvent evaporated, resistates is dissolved in methylene dichloride.It is inferior that solution with water is given a baby a bath on the third day after its birth, and uses anhydrous magnesium sulfate drying, and evaporate to dryness.Resistates is dissolved in ethyl acetate, and solution filtered through silica gel, and evaporate to dryness obtain 23.7 gram 1-(4-chloro-phenyl-)-2-pyridin-4-yl-second diketone, fusing point 119-120 ℃.
B. benzaldehyde derivative (formula III compound)
2-bromo-6-tolyl aldehyde
(i) solution that 9.52 gram (2-bromine benzylidene) aniline is dissolved in 150 milliliters of acetate formation is handled with 7.9 gram acid chlorides (II).Mixture heating up was refluxed 1 hour, pour into then in 150 ml waters, with methylene dichloride extracting three times.The organic extract of bonded washes with water, uses anhydrous magnesium sulfate drying, is evaporated to dried.Resistates is chromatography on silica gel, makes elutriant with methylene chloride (99: 5), obtains 10.3 grams, two [acetate moiety closes (3-bromo-2-phenylimino methyl-phenyl) palladium] (Pd-Pd), fusing point 199-200 ℃.
(ii) the solution that 10.3 grams, two [acetate moiety closes (3-bromo-2-phenylimino methyl-phenyl) palladium] (Pd-Pd) is dissolved in 80 milliliters of methylene dichloride and 80 milliliters of acetone formation is handled with 90 milliliters of saturated nacl aqueous solutions while stirring.After 10 minutes, the filtering solid obtains 6.1 grams, two [chlorine (3-bromo-2-phenyl-iminomethyl phenyl) palladiums] (Pd-Pd), fusing point 280-282 ℃.
(iii) 6.1 grams, two [chlorine (3-bromo-2-phenyl-iminomethyl phenyl) palladiums] (Pd-Pd) being dissolved in the solution that forms in 225 milliliters of purified petroleum benzin handles in argon gas with 7.9 gram triphenylphosphines.Subsequently, mixture was at room temperature stirred 30 minutes.Dropwise add 12.5 milliliters of lithium methides on 0 ℃ of following stirring limit and be dissolved in the 1.6M solution that forms in the ether, at room temperature mixture was stirred 1 hour subsequently.Use 225 milliliters of 1N hydrochloric acid 0 ℃ of following treating mixture then, filter and clean solid with ether.The organic extract of bonded washes twice with water, uses anhydrous magnesium sulfate drying, is evaporated to dried.Resistates is chromatography on silica gel, makes elutriant with hexane/ethyl acetate (98: 2), obtains 0.7 gram 2-bromo-6-tolyl aldehyde, fusing point 48-49 ℃.
2,6-di-isopropyl phenyl aldehyde
The solution that forms among the 1.6M that 6.8 milliliters of butyllithiums are formed in hexane dropwise adds 2.6 gram 2-bromo-1 on-78 ℃ of following limits of stirring, and the 3-diisopropyl benzene is dissolved in the solution that forms in 16 milliliters of tetrahydrofuran (THF)s.Mixture was stirred 30 minutes under same temperature, be dissolved in the solution-treated that forms in 1.5 milliliters of tetrahydrofuran (THF)s with 1.3 gram N-formyl radical-piperidines subsequently.Then, rise to room temperature with 6 hours time chien shih mixture.Mixture is cooled to 0 ℃ also with the acid treatment of 12 milliliters of 3N salt.With aqueous solution extracting four times, the organic extract of bonded cleans with saturated nacl aqueous solution, uses anhydrous magnesium sulfate drying, is evaporated to dried with ether.Resistates is chromatography on silica gel, makes elutriant with methylene dichloride, obtains 1.07 gram butyrous 2,6-di-isopropyl phenyl aldehyde.
2,6-dimethyl-3-nitrobenzaldehyde
At room temperature restrain 2 with 15 fens clock times with 2, the 6-dimethylbenzaldehyde adds in the mixture of 20 milliliters of concentrated nitric acids and 10 milliliters of acetate.Subsequently, mixture was at room temperature stirred 5 minutes, be poured on the frozen water.Again mixture was stirred 5 minutes, filter and resistates is dissolved in the methylene dichloride.Behind anhydrous magnesium sulfate drying, solvent is evaporated.Resistates is chromatography on silica gel, makes elutriant with hexane/ethyl acetate, obtains 1.23 grams 2,6-dimethyl-3-nitrobenzaldehyde, fusing point 54-57 ℃ (from hexane) and 0.33 gram 2,6-dimethyl-3,5-dinitrobenzal-dehyde, fusing point 119-122 ℃ (from toluene/hexane).
2,4,6-trimethylammonium-3-morpholine-4-base-tolyl aldehyde
With 0.98 gram 3-chloromethyl-2,4,6-trimethylammonium-phenyl aldehyde is dissolved in the solution that forms in 20 milliliters of acetonitriles to be handled with 0.87 milliliter of morpholine.Mixture was at room temperature stirred 4 hours subsequent filtration.Solvent is evaporated, and resistates is dissolved in ethyl acetate.With the solution with water washed twice, with evaporate to dryness behind the anhydrous magnesium sulfate drying.Distillation residue obtain 1.05 grams 2,4,6-trimethylammonium-3-morpholine-4-base-methyl-phenyl aldehyde, 150 ℃/0.3Torr of boiling point.
3-dimethylaminomethyl-2,4, the 6-trimethylbenzaldehyde
With being similar to above-mentioned preparation 2,4, the method for 6-trimethylammonium-3-morpholine-4-base-tolyl aldehyde prepares 3-dimethylaminomethyl-2,4,6-trimethylbenzaldehyde, 150 ℃/0.3Torr of boiling point.
2,4,6-trimethylammonium-3-(4-methylpiperazine-1-base-methyl)-phenyl aldehyde
With with above-mentioned preparation 2,4,6-trimethylammonium-3-morpholine-similar mode of 4-base-tolyl aldehyde prepares 2,4,6-trimethylammonium-3-(4-methylpiperazine-1-base-methyl)-phenyl aldehyde, 90 ℃ of fusing points (in acetonitrile).
3-hydroxyl-2, the 6-dimethylbenzaldehyde
(i) with 2.8 grams 2,6-dimethyl-3-nitrobenzaldehyde is dissolved in the solution that forms in 150 milliliters of toluene to be handled with 5 milliliters of ethylene glycol and 20 milligrams of tosic acid.Mixture heating up was refluxed 18 hours, with separator with water sepn.Mixture is cooled to room temperature, and washes with water twice.With solvent evaporated behind the anhydrous magnesium sulfate drying, the crystallization resistates is crystallized out from hexane.Obtain 3.0 gram 2-(2,6-dimethyl-3-nitrophenyl)-1,3-dioxolane, fusing point 69-71 ℃.
(ii) with 2.7 gram 2-(2,6-dimethyl-3-nitrophenyl)-1, the 3-dioxolane is dissolved in the hydrogenation 45 minutes under the condition that 0.2 gram platinum oxide exists of the solution that forms in 30 milliliters of ethyl acetate.Filtration catalizer, concentrated solution obtain the crystallization resistates.Recrystallization obtains 2.35 gram 2-(3-amino-2,6-3,5-dimethylphenyl)-1,3-dioxolane, fusing point 100-103 ℃ from hexane.
(iii) following to 15 fens clock times at 0 ℃, 0.73 gram SODIUMNITRATE is dissolved in the solution that forms in 2 ml waters adds 2.0 gram 2-(3-amino-2 while stirring, the 6-3,5-dimethylphenyl)-1, the 3-dioxolane is dissolved in the suspension that forms in 1.9 milliliters of vitriol oils and 5.5 ml waters.Subsequently, mixture was at room temperature stirred 15 minutes, join while stirring in the mixture of 1 milliliter of vitriol oil and 15 ml waters with 5 fens clock times down at 110 ℃.While stirring mixture heating up was refluxed 1 hour, be cooled to room temperature then, filter and wash with water, obtain 1.55 gram 3-hydroxyls-2,6-dimethylbenzaldehyde, fusing point 159-165 ℃ (from isopropyl ether).
3-diethylamino methyl-2,4, the 6-trimethylbenzaldehyde
3-diethylamino methyl-2,4, the 6-trimethylbenzaldehyde, 200 ℃/0.2Torr of boiling point uses and Synthetic 2, and 4, the similar method preparation of 6-trimethylammonium-3-morpholine-4-base-tolyl aldehyde.
(2RS, 6RS)-and (2R, 6S)-3-(2,6-thebaine-4-base-methyl)-2,4, the 6-trimethylbenzaldehyde
With with above-mentioned Synthetic 2,4, the preparation of the similar method of 6-trimethylammonium-3-morpholine-4-base-methyl-phenyl aldehyde (2RS, 6RS)-and (2R, 6S)-3-(2,6-thebaine-4-base-methyl)-2,4,6-trimethylbenzaldehyde, 130 ℃ of fusing points (hexane).
The production method of embodiment A-E explanation pharmaceutical preparations.
Embodiment A
Hard gelatin capsule can be prepared as follows:
Composition milligram/capsule
1. the spray powder end 20 of containing 75% Compound I
2. sodium 0.2
3. Xylo-Mucine 4.8
4. Microcrystalline Cellulose 86.0
5. talcum 8.0
6. Magnesium Stearate 1.0
Total amount 120
Will be based on activeconstituents, gelatin and Microcrystalline Cellulose, the spray powder end of average activity composition particulate size<1 μ (measuring) with the self-checkign n. optical spectroscopy, wetting and knead with Xylo-Mucine and the dioctyl sodium sulphosuccinate aqueous solution.Agglomerate granulating, the drying of gained also sieved, and particle and Microcrystalline Cellulose, talcum and the Magnesium Stearate that obtains mixed.Powder is inserted capsule No. 0.
Embodiment B
Tablet can be prepared as follows:
Composition milligram/tablet
1. the fine grinding powder 20 of Compound I
2. lactose powder 100
3. white W-Gum 60
4.Povidone K30 8
5. white cornstarch 112
6. talcum 16
7. Magnesium Stearate 4
Total amount 320
The material of fine grinding is mixed with lactose and a part of W-Gum.With Povidone K30 that mixture is wetting and knead, agglomerate granulating, the drying of gained also sieved.Particle is mixed with remaining W-Gum, talcum and Magnesium Stearate, be pressed into the tablet of suitable size.
Embodiment C
Soft gelatin capsule can be prepared as follows:
Composition milligram/capsule
1. Compound I 5
2. triglyceride level 450
Total amount 455
Digest compound I with 10 and dissolve in while stirring in the 90 gram medium chain triglycerides, rare gas elementization, against sunshine.This solution is processed to contain the soft gel capsule of 5 milligrams of activeconstituentss as capsule filling.
Embodiment D
Creme can be prepared by following composition according to himself mode:
Weight %
Formula I compound 0.1-5
Hexadecanol 5.25-8.75
Arlacel 165 (glycerine/PEG 100 stearic acid 3.75-6.25 esters)
Miglyol 818 (the sweet 11.25-18.75 oil of caprylic/capric/linolic acid three esters
Sorbitol Solution USP 3.75-6.25
Na
2EDTA 0.075-0.125
Carbopol 934P(carbomer 934P) 0.15-0.25
Butylated hydroxyanisol 0.0375-0.0625
Para methyl paraben 0.135-0.225
Propylparaben 0.0375-0.0625
NaOH (10% solution) 0.15-0.25
Water, an amount of 100.00
Embodiment E
Gel can be prepared by following composition according to himself mode:
Weight %
Formula I compound 0.1-5
Pluronic L 101(poloxamer 331) 10.00
Aerosil 200 (silicon-dioxide) 8.00
PCL liquid (fatty acid ester) 15.00
Cetiol V (decyl oleate) 20.00
Neobee oil (middle chain length triglyceride level) 15.00
Euhanol G (Standamul G), an amount of 100.00
By changing the ratio of adjuvant among embodiment D and the E, can change the physical property of prepared product.
Claims (16)
1. the imdazole derivatives of following general formula and pharmaceutical salts thereof:
R wherein
1Expression C
1-C
6Alkyl or halogen, R
2Expression hydrogen, hydroxyl, nitro, C
1-C
6Carbalkoxy, two (C
1-C
6Alkyl) amino-C
1-C
6Alkyl, morpholino C
1-C
6Alkyl or 4-methylpiperazine base-C
1-C
6Alkyl, R
3Expression hydrogen or C
1-C
6Alkyl, R
5Expression amino or C
1-C
6Alkyl, R
7Expression hydrogen or C
1-C
6Alkyl, R
8The expression hydrogen or halogen.
2. the compound in the claim 1, it is 4-[5-(4-chloro-phenyl-)-2-(2,4, the 6-trimethylphenyl) imidazol-4 yl] pyridine.
3. the compound in the claim 1, it is 4-[5-(3-aminomethyl phenyl)-2-(2,4, the 6-trimethylphenyl) imidazol-4 yl] pyridine.
4. the compound in the claim 1, it is 3-chloro-2-[4-(4-chloro-phenyl-)-5-pyridin-4-yl-imidazoles-2-yl] aniline.
5. the compound in the claim 1, it is 4-[5-(4-chloro-phenyl-)-2-(2, the 6-diisopropyl phenyl) imidazol-4 yl] pyridine.
6. the compound in the claim 1, it is 3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-the mesitylene carboxylic acid methyl esters.
7. the compound in the claim 1, it is 4-[3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl] morpholine.
8. the compound in the claim 1, it is [3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl] dimethylamine.
9. the compound in the claim 1, it is 1-[3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl]-the 4-methylpiperazine.
10. the compound in the claim 1, it is 4-[5-(4-chloro-phenyl-)-2-(2,4,6-trimethylammonium-3-nitrophenyl) imidazol-4 yl] pyridine.
11. the compound in the claim 1, it is 3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2.
12. the compound in the claim 1, it is 4-[5-(4-fluorophenyl)-2-(2-bromo-6-aminomethyl phenyl)-imidazol-4 yl]-pyridine.
13. the compound in the claim 1, it is:
4-[5-(4-fluorophenyl)-2-(2,4, the 6-trimethylphenyl) imidazol-4 yl] pyridine,
4-[5-(4-chloro-phenyl-)-2-(2, the 6-3,5-dimethylphenyl) imidazol-4 yl] pyridine,
4-[5-(4-chloro-phenyl-)-2-(2-chloro-6-aminomethyl phenyl) imidazol-4 yl] pyridine,
4-[5-(4-chloro-phenyl-)-2-(2-bromo-6-aminomethyl phenyl) imidazol-4 yl] pyridine,
4-[5-(4-chloro-phenyl-)-2-(2,6-dimethyl-3-nitrophenyl) imidazol-4 yl] pyridine,
3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2, the 4-xylenol, or
(2RS, 6RS)-and (2R, 6S)-4-[3-[5-(4-chloro-phenyl-)-4-pyridin-4-yl-imidazoles-2-yl]-2,4, the 6-trimethyl benzyl]-2, the 6-thebaine.
14. pharmaceutical preparations, it contains the compound and the pharmaceutical carrier of arbitrary claim among the claim 1-13.
15. a method for preparing the compound of claim 1, it comprises R wherein
7And R
8Implication and claim 1 in the diketone of identical following general formula:
With R wherein
1, R
2, R
3And R
5Implication and claim 1 in the aldehyde of identical following general formula:
Under the condition that ammonia exists, react; the hydroxy-protective group that removal may exist; if the words that need; reactive group in the resulting formula I compound is carried out functionalized modification; and if the words that need; formula I compound is transformed into pharmaceutical salts, and the oh group in the compound of formula III can exist with protected form.
16. the application of the compound of claim 1 in producing pharmaceutical preparations, that described pharmaceutical preparations is used for the treatment of is atherosis with prevention of arterial, psoriatic, tumour or alopecia.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH3768/942 | 1994-12-13 | ||
CH376894 | 1994-12-13 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1175252A CN1175252A (en) | 1998-03-04 |
CN1145623C true CN1145623C (en) | 2004-04-14 |
Family
ID=4263074
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB951976281A Expired - Fee Related CN1145623C (en) | 1994-12-13 | 1995-12-01 | Imidazole derivatives as protein kinase inhibitors in particular egf-rthyrosine kinase |
Country Status (16)
Country | Link |
---|---|
US (1) | US5959113A (en) |
EP (1) | EP0797575B1 (en) |
JP (1) | JPH10510281A (en) |
CN (1) | CN1145623C (en) |
AR (1) | AR003406A1 (en) |
AT (1) | ATE252094T1 (en) |
AU (1) | AU4301096A (en) |
BR (1) | BR9509998A (en) |
CA (1) | CA2207404C (en) |
DE (1) | DE69531956T2 (en) |
DK (1) | DK0797575T3 (en) |
ES (1) | ES2208698T3 (en) |
FI (1) | FI972492A0 (en) |
PT (1) | PT797575E (en) |
TR (1) | TR199501561A2 (en) |
WO (1) | WO1996018626A1 (en) |
Cited By (1)
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CN101080399B (en) * | 2005-02-18 | 2012-12-12 | 独立行政法人科学技术振兴机构 | Process for producing optically active epoxy compound, complex for use in the process, and process for producing the same |
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US6083949A (en) * | 1995-10-06 | 2000-07-04 | Merck & Co., Inc. | Substituted imidazoles having anti-cancer and cytokine inhibitory activity |
AU728760B2 (en) * | 1996-11-20 | 2001-01-18 | Merck & Co., Inc. | Triaryl substituted imidazoles, compositions containing such compounds and methods of use |
WO1998022109A1 (en) * | 1996-11-20 | 1998-05-28 | Merck & Co., Inc. | Triaryl substituted imidazoles as glucagon antagonists |
US5880139A (en) * | 1996-11-20 | 1999-03-09 | Merck & Co., Inc. | Triaryl substituted imidazoles as glucagon antagonists |
US6022884A (en) | 1997-11-07 | 2000-02-08 | Amgen Inc. | Substituted pyridine compounds and methods of use |
AU4506399A (en) * | 1998-06-05 | 1999-12-30 | Novartis Ag | Aryl pyridinyl thiazoles |
AU4395399A (en) * | 1998-07-02 | 2000-01-24 | Sankyo Company Limited | Five-membered heteroaryl compounds |
JP3850596B2 (en) | 1999-02-25 | 2006-11-29 | 本州化学工業株式会社 | Novel partially protected trisphenols and process for their production |
WO2003024447A1 (en) * | 2001-09-20 | 2003-03-27 | Smithkline Beecham Corporation | Inhibitors of glycogen synthase kinase-3 |
US6790852B2 (en) * | 2002-04-18 | 2004-09-14 | Hoffmann-La Roche Inc. | 2-(2,6-dichlorophenyl)-diarylimidazoles |
ES2497116T3 (en) | 2002-08-19 | 2014-09-22 | Lorus Therapeutics Inc. | 2,4,5-trisubstituted imidazoles and their use as antimicrobial agents |
CN100436450C (en) * | 2003-10-16 | 2008-11-26 | 霍夫曼-拉罗奇有限公司 | Novel triarylimidazoles |
US7144889B2 (en) | 2003-10-16 | 2006-12-05 | Hoffman-La Roche Inc. | Triarylimidazoles |
US7169781B2 (en) * | 2003-10-17 | 2007-01-30 | Hoffmann-La Roche Inc. | Imidazole derivatives and their use as pharmaceutical agents |
AU2004289539C1 (en) | 2003-11-14 | 2012-06-07 | Lorus Therapeutics Inc. | Aryl imidazoles and their use as anti-cancer agents |
US8148392B2 (en) | 2005-05-25 | 2012-04-03 | Lorus Therapeutics Inc. | 2-indolyl imidazo [4,5-d] phenanthroline derivatives and their use in the treatment of cancer |
JP5283872B2 (en) * | 2006-09-27 | 2013-09-04 | シスメックス株式会社 | Method for evaluating growth inhibitory effect of inhibitor on tumor cell, and method for screening for compound inhibiting tumor cell growth |
WO2008042216A2 (en) * | 2006-09-28 | 2008-04-10 | Follica, Inc. | Methods, kits, and compositions for generating new hair follicles and growing hair |
JP2016516082A (en) | 2013-03-20 | 2016-06-02 | アプトース バイオサイエンシーズ, インコーポレイテッド | 2-Substituted imidazo [4,5-D] phenanthroline derivatives and their use in the treatment of cancer |
DK3052102T3 (en) | 2013-10-04 | 2020-03-09 | Aptose Biosciences Inc | CANCER TREATMENT COMPOSITIONS |
US9394236B2 (en) | 2014-02-03 | 2016-07-19 | Quadriga Biosciences, Inc. | β-substituted γ-amino acids and analogs as chemotherapeutic agents |
SG10201710436WA (en) | 2014-02-03 | 2018-01-30 | Quadriga Biosciences Inc | Beta-substituted beta-amino acids and analogs as chemotherapeutic agents |
ES2926931T3 (en) * | 2014-02-07 | 2022-10-31 | Agency Science Tech & Res | Casein kinase 1 inhibitors based on 2,4,5-tri-substituted azoles as inducers of cardiomyogenesis |
TWI665178B (en) | 2015-08-03 | 2019-07-11 | 夸德里加生物科學公司 | Beta-substituted beta-amino acid and analogue as chemotherapeutic agent and application thereof |
CN109212045A (en) * | 2017-07-04 | 2019-01-15 | 万全万特制药(厦门)有限公司 | The method of separating and assaying of escitalopram oxalate residual solvent and impurity |
KR20200096914A (en) | 2017-10-30 | 2020-08-14 | 압토스 바이오사이언시스 인코포레이티드 | Aryl imidazole for cancer treatment |
CN114262298B (en) * | 2021-12-03 | 2023-09-26 | 郑州轻工业大学 | 2-bromo-4-N, N-dimethylaminoimidazole and preparation method thereof |
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US3707475A (en) * | 1970-11-16 | 1972-12-26 | Pfizer | Antiinflammatory imidazoles |
US3940486A (en) * | 1971-05-10 | 1976-02-24 | Ciba-Geigy Corporation | Imidazole derivatives in the treatment of pain |
CH561716A5 (en) * | 1971-05-10 | 1975-05-15 | Ciba Geigy Ag | |
MC2096A1 (en) * | 1989-02-23 | 1991-02-15 | Hoffmann La Roche | SUBSTITUTED PYRROLES |
EP0624159B1 (en) * | 1992-01-13 | 1998-11-25 | Smithkline Beecham Corporation | Pyridyl substituted imidazoles |
MX9300141A (en) * | 1992-01-13 | 1994-07-29 | Smithkline Beecham Corp | NOVEL IMIDAZOLE COMPOUNDS, PROCEDURE FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT. |
HUT71553A (en) * | 1992-08-06 | 1995-12-28 | Warner Lambert Co | 2-thioindoles (selenoindoles) and related disulfides (selenides) which inhibit protein tyrosine kinases and which have antitumor properties |
WO1995003297A1 (en) * | 1993-07-21 | 1995-02-02 | Smithkline Beecham Corporation | Imidazoles for treating cytokine mediated disease |
NZ274063A (en) * | 1993-09-17 | 1997-11-24 | Smithkline Beecham Corp | Cytokine suppressive anti-inflammatory drug binding protein (csbp) and its use |
-
1995
- 1995-12-01 EP EP95941646A patent/EP0797575B1/en not_active Expired - Lifetime
- 1995-12-01 ES ES95941646T patent/ES2208698T3/en not_active Expired - Lifetime
- 1995-12-01 US US08/860,750 patent/US5959113A/en not_active Expired - Fee Related
- 1995-12-01 BR BR9509998A patent/BR9509998A/en not_active IP Right Cessation
- 1995-12-01 PT PT95941646T patent/PT797575E/en unknown
- 1995-12-01 JP JP8518206A patent/JPH10510281A/en not_active Ceased
- 1995-12-01 DE DE69531956T patent/DE69531956T2/en not_active Expired - Fee Related
- 1995-12-01 AU AU43010/96A patent/AU4301096A/en not_active Abandoned
- 1995-12-01 CN CNB951976281A patent/CN1145623C/en not_active Expired - Fee Related
- 1995-12-01 DK DK95941646T patent/DK0797575T3/en active
- 1995-12-01 CA CA002207404A patent/CA2207404C/en not_active Expired - Fee Related
- 1995-12-01 WO PCT/EP1995/004741 patent/WO1996018626A1/en active IP Right Grant
- 1995-12-01 AT AT95941646T patent/ATE252094T1/en not_active IP Right Cessation
- 1995-12-11 AR ARP950100495A patent/AR003406A1/en unknown
- 1995-12-12 TR TR95/01561A patent/TR199501561A2/en unknown
-
1997
- 1997-06-12 FI FI972492A patent/FI972492A0/en not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101080399B (en) * | 2005-02-18 | 2012-12-12 | 独立行政法人科学技术振兴机构 | Process for producing optically active epoxy compound, complex for use in the process, and process for producing the same |
Also Published As
Publication number | Publication date |
---|---|
CN1175252A (en) | 1998-03-04 |
DE69531956T2 (en) | 2004-07-29 |
FI972492A (en) | 1997-06-12 |
JPH10510281A (en) | 1998-10-06 |
AU4301096A (en) | 1996-07-03 |
FI972492A0 (en) | 1997-06-12 |
EP0797575A1 (en) | 1997-10-01 |
ES2208698T3 (en) | 2004-06-16 |
CA2207404C (en) | 2004-06-29 |
BR9509998A (en) | 1997-12-30 |
US5959113A (en) | 1999-09-28 |
CA2207404A1 (en) | 1996-06-20 |
WO1996018626A1 (en) | 1996-06-20 |
DE69531956D1 (en) | 2003-11-20 |
DK0797575T3 (en) | 2004-02-16 |
ATE252094T1 (en) | 2003-11-15 |
AR003406A1 (en) | 1998-08-05 |
PT797575E (en) | 2004-02-27 |
EP0797575B1 (en) | 2003-10-15 |
MX9704263A (en) | 1997-09-30 |
TR199501561A2 (en) | 1996-07-21 |
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